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Synaptic scaling mediated by glial TNF-α

Abstract

Two general forms of synaptic plasticity that operate on different timescales are thought to contribute to the activity-dependent refinement of neural circuitry during development: (1) long-term potentiation (LTP) and long-term depression (LTD), which involve rapid adjustments in the strengths of individual synapses in response to specific patterns of correlated synaptic activity, and (2) homeostatic synaptic scaling, which entails uniform adjustments in the strength of all synapses on a cell in response to prolonged changes in the cell's electrical activity1,2. Without homeostatic synaptic scaling, neural networks can become unstable and perform suboptimally1,2,3. Although much is known about the mechanisms underlying LTP and LTD4, little is known about the mechanisms responsible for synaptic scaling except that such scaling is due, at least in part, to alterations in receptor content at synapses5,6,7. Here we show that synaptic scaling in response to prolonged blockade of activity is mediated by the pro-inflammatory cytokine tumour-necrosis factor-α (TNF-α). Using mixtures of wild-type and TNF-α-deficient neurons and glia, we also show that glia are the source of the TNF-α that is required for this form of synaptic scaling. We suggest that by modulating TNF-α levels, glia actively participate in the homeostatic activity-dependent regulation of synaptic connectivity.

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Figure 1: TNF-α signalling is not required for CA1 hippocampal LTP or LTD.
Figure 2: TNF-α mediates synaptic scaling during activity blockade.
Figure 3: Tnf -/- neurons scale down but not up following activity manipulations.
Figure 4: Glia are the source of TNF-α required for synaptic scaling during activity blockade.

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Acknowledgements

We thank S. Wu for expert technical assistance, J. Tsui and B. Stevens for advice on tissue culture techniques, W. Xu, P. Luu and W. Morishita for discussions, and R. Huganir and B. Barres for reagents. This work was funded by NIH grants to R.C.M. and D.S. Author Contributions D.S. performed the experiments and data analyses. D.S. and R.C.M. designed the experiments, discussed the interpretation of results and co-wrote the paper.

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Correspondence to Robert C. Malenka.

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Stellwagen, D., Malenka, R. Synaptic scaling mediated by glial TNF-α. Nature 440, 1054–1059 (2006). https://doi.org/10.1038/nature04671

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